Implant and Production Method for Said Implant

ABSTRACT

The invention relates to an implant, e.g. a stent, bone replacement material, a prosthesis, a scaffold or similar, which comprises a coating at least in those surface areas that come into contact with hard and/or soft tissue when implanted. To ensure that the active ingredient contained in the coating (bisphosphonate) is released into the surrounding tissue or can act in the latter in a controlled manner at the correct speed, the coating is characterised in that it contains bisphosphonate, the respective pharmaceutically compatible salts or esters of the latter, in addition to at least one amphiphilic component, selected from the group containing branched or linear, substituted or unsubstituted, saturated or partially unsaturated C10-C30 alkyl-, alkenyl, alkylaryl-, aryl-, cycloalkyl-, alkylcycloalkyl-, alkylcycloaryl-carboxylates, -phosphates or -sulfates or mixtures thereof and/or a water-soluble ionic polymer component. The invention also relates to a method for producing an implant of this type and to a specific composition, which can be used to produce a coating of this type.

TECHNICAL FIELD

The present invention concerns an implant, which in at least some areasis provided with a coating in surface areas which in an implanted stateare in contact with hard and/or soft tissue.

BACKGROUND OF THE INVENTION

Injured or damaged parts of the hard and/or soft tissue of the humanbody are restored or mechanically reinforced the best by usingautologous hard and/or soft tissue. This is not always possible forvarious reasons, which is why in many cases synthetic material is usedas a temporary (biodegradable or post-operatively removable) orpermanent replacement material.

Implants which are anchored in the hard and/or soft tissue serve thetemporary or permanent replacement or the support of parts of the humanbody which have been impaired by accident, abrasion, deficiency orsickness or otherwise degenerated. Normally, an implant is referred toas an artificial, chemically stable material which is introduced intothe body as a plastic replacement or for mechanical reinforcement (seee.g. Roche Lexikon Medizin, Urban & Fischer (Eds.); 5^(th) edn. 2003).The support- and replacement function in the body is taken over on thebasis of the mechanical characteristics and the implant design.Therefore, for instance the hip- and knee joint prostheses, spinalimplants and vessel prostheses have been successfully used clinicallyfor many years. For the anchoring of the implant and the implanttolerance at the interface implant surface/neighboring tissue, theimplant surface has a great significance. By a change of the implantsurface, the recovery process can be accelerated.

Various methods are used for surface treatment and surface structuring,as e.g. Titanium in Medicine, Material Science, Surface Science,Engineering, Biological Responses and Medical Applications Series:Engineering Materials, (Brunette, D. M.; Tengvall, P.; Textor, M.;Thomsen, P. (Eds.)); and the references cited therein.

The increase of roughness is for example well established (for many, seeTitanium in Medicine, Material Science, Surface Science, Engineering,Biological Responses and Medical Applications Series: EngineeringMaterials, (Brunette, D. M.; Tenvall, P.; Textor, M.; Thomsen, P.(Eds.)).

Furthermore, papers exist which describe the chemical modification ofimplant surfaces in order to achieve a better connection of the bone tothe implant surface (Xue W., Liu X, Zheng X, Ding C, Biomaterials. 2005Jun; 26 (16): 3029-37).

More recent approaches are pharmaceutical modifications of the surfacein order to accelerate the osseointegration of the implants and/or topromote or to stimulate the regeneration of the surrounding hard and/orsoft tissue, e.g. with growth factors (Raschke M J, Schmidmaier G.Unfallchirurg. 2004 August; 107(8): 653-63).

By contrast, layers loaded with active substances can serve to preventunwished reactions to implants, for example vessel prostheses(Hausleiter J, et al., Eur. Heart J. 2005 August; 26(15): 1475-81. Epub2005 Jun. 23).

Other medication groups interesting for pharmaceutical surfacemodification are pharmaceuticals which were developed for the systemictreatment of osteoporosis, as for example calcitonin, strontiumranelateand various bisphosphonates.

Bisphosphonates can be interpreted as structural analogs ofpyrophosphate, in which the P-O-P-group is replaced by an enzymaticallystable P-C-P-group. By substitution of the hydrogen atoms at the C-atomof the P-C-P-group, bisphosphonates with various structural elements andcharacteristics are available. Known bisphosphonates which have beenapproved for clinical use are e.g. pamidronic acid, alendronic acid,ibandronic acid, clodronic acid or etidronic acid. In medicine,bisphosphonates have been established in the treatment of metabolic bonediseases, especially tumor-associated hypercalcemias, osteolytic bonemetastases and postmenopausal and glucocortico-induced osteoporoses.Furthermore, tests show that bisphosphonates can be used for theprevention or for the treatment of vascular restenosis (WO 02/003677).

Depending on their structure, some of the known bisphosphonates clearlydiffer among each other with respect to their therapeutic efficacy.Especially those bisphosphonates which have an amino-function betweenthe two phosphorus-atoms in the structural unit have a high therapeuticefficacy. Below, these compounds are referred to asamino-bisphosphonates.

The pharmacological action of the bisphosphonates is based on a highaffinity to calcium phosphate structures of the bone surface, whereinsubsequently bone-degrading cells (osteoclasts) are inhibited, whichleads to a decrease of the bone resorption and simultaneously to areactivation of bone-developing cells (osteoblasts). Due to the specialpharmacokinetics of the bisphosphonates, a local therapy is preferredcompared to the systemic administration.

Based on this knowledge, in the past years, numerous tests wereconducted in which the immobilisation of selected bisphosphonates onhard tissue implants and their impact on the ingrowth-behavior of thecorresponding implant were tested. Thus, e.g. in U.S. Pat. No. 5,733,564the coating of materials (endoprostheses, screws, pins, etc.) withaqueous bisphosphonate-solutions were described with the aim toaccelerate the bone-regeneration around the implant. However, the pooradhesion of the bisphosphonates on metallic surfaces and theirsolubility in water constitute a disadvantage of this approach.

Yoshinari et al. (Biomaterials 23 (2002), 2879-2885) showed by means ofin vivo studies that calciumphosphate-coated implants of pure titanium,which had been impregnated with an aqueous pamidronate-solution, showedan improved osteogenesis at the implant surface compared to implantswhich had not been impregnated with pamidronate. Due to the highaffinity of the bisphosphonates to calcium ion-containing substrates,calciumphosphate surfaces constitute a possible substrate for theimmobilisation of bisphosphonates, as on these surfaces thebioavailability of the bisphosphonates and thus their therapeuticalefficacy by their interaction with calcium ions is present at a higherrate than on surfaces essentially free of calcium ions.

WO-A-02/04038 describes a further variant of the immobilisation ofbisphosphonates in hydroxyapatite-containing coatings of bone implants.Because metallic implants play a dominating role in the hard tissue areaand on the other hand a calcium phosphate coating of metallic surfacesentails increased production expenses, in the past, numerous attemptswere made to modify metallic implant materials such that an effectivebisphosphonate-immobilisation is enabled thereon.

Therefore, studies became known in which calcium ions are brought intothe surface of titanium implants by electron beam-implantation (JP2000070288, H. Kajiwara et al. Biomaterials 26 (2005), 581-587), inorder to achieve an improved adhesion of bisphosphonates. However, thismethod has the disadvantage of high apparatus-related expenses.

Further studies concern the electrolytic separation ofcalcium-etidronate on pure titanium (K. Duan et al., J. Biomed. Mater.Res.: Appl. Biomater. 72B (2005), 43-51), wherein on the one hand thinfilms of bisphosphonate were able to be separated, however, they showedinhomogeneities and signs of shrinking during the drying process.

In WO-A-2005/018699, bisphosphonate-coated metallic implants aredescribed, which were produced in a way that first, a protein layer, forexample of fibrinogen is immobilized on the metallic surface.Subsequently, one or more bisphosphonates are covalently bound to thisprotein layer via reactive functional groups. A significant disadvantageof this method lies in the use of toxic reagents during theimmobilisation or cross-linking, respectively, of the protein layer andthe covalent coupling of the bisphosphonate.

SUMMARY OF THE INVENTION

One object of the invention is therefore, among others, to provide animproved implant, which e.g. shows a good and complication-freeosteointegration, and which still can be produced in a simple andcost-efficient process.

One solution to this is for instance achieved in that at least in someareas the implant is provided with a coating in surface areas which inan implanted state are at least indirectly in contact with hard and/orsoft tissue. At least indirectly in contact herein means that thecoating can be in direct contact with the hard and/or the soft tissue,or over channels, openings, and/or a further layer or layers, whichhowever do not or only marginally influence or change, respectively, therelease characteristics of the bisphosphonate described below. Thiscoating contains at least a bisphosphonate of the general formula(H₂O₃P)—CXY—(PO₃H₂), wherein X is selected from H, OH, Cl, F, or amethyl group, Y is selected from H, Cl, F, NH₂, or a linear or abranched C1-C20 alkyl group (preferably C1-C10, more preferably C1-C7),which is unsubstituted or preferably substituted by NH₂, N(CH₃)₂,NH(CH₃), N(CH₃)₃, pyridinyl or imidazolyl, wherein one or more carbonatoms can be replaced by hetero atoms selected from the group —NR¹—, —S—or —O—, wherein R¹ is selected from —H or —CH₃, with the proviso that notwo hetero atoms are interconnected, or pharmaceutically compatiblesalts or esters of the latter, in addition to at least one amphiphiliccomponent selected from the group of branched or linear, substituted orunsubstituted, saturated or partially unsaturated C10-C30 alkyl-,alkenyl-, alkylaryl-, aryl-, cycloalkyl-, alkylcycloalkyl-,alkylcykloaryl-carboxylates, -phosphates, or -sulfates or mixturesthereof, and/or a water-soluble ionic polymeric component.

Also mixtures of various such bisphosphonates are possible, as well asmixtures of various amphiphilic components, or water-soluble ionicpolymeric components, respectively.

As substituents for the alkyl group of Y also kationic C2-C5 ammoniumderivates are possible, such as e.g. N(CH₂CH₃)₃.

Preferably, Y is a linear C1-C7 alkyl group substituted by NH₂, N(CH₃)₂,NH(CH₃), N(CH₃)₃, pyridinyl or imidazolyl. The amphiphilic componentmore preferably is a linear unsubstituted C10-C20 alkyl-carboxylate oralkyl-sulfate.

One of the gists of the invention thus is to mix or bind, respectively,the bisphosphonate, which, without taking specific measures is toomobile in aqueous solutions due to the strong solubility and which,after the fixture of the implant, would be carried away from the surfacetoo soon, with a second component in a composite salt, which has theconsequence that this composite salt, which has a significantly lowersolubility in water, and therefore also in the physiological environmentafter the fixture of the implant, therefore can exert its efficacy atthe decisive surface over a significantly longer time span. It is notedthat while using the coating according to the invention, theavailability of the bisphosphonate present in the coating surprisinglyis warranted at the implant surface or in the direct environment of theimplant, respectively, during several days to weeks. Surprisingly, thiscan be achieved by a specific selection of additional components. Theamphiphilic component, or the bisphosphonate and the water-soluble ionicpolymeric component, respectively, are present as a mixture, preferablyas a composite salt (i.e. the amphiphilic component is also ionic) witha low solubility in water, and it shows that by the use of the specificamphiphilic or water-soluble ionic polymeric component, an astonishinglygood adhesion of the bisphosphonate on prevalent implant materials isachievable. Preferably, the coating is a dry coating. The presentinvention is based on the idea that the release of a low-molecular agentfrom an implant coating into the surrounding, in case of an implantaqueous environment, is significantly determined by its diffusion fromthe dry layer into the environment, and that this release itself isdetermined by the solubility of the agent in the surrounding aqueousmedium. Bisphosphonates usually are compounds which are well soluble inwater, such that one can count with a fast diffusion from ahumidification and similarly from a dry coating and therefore with a lowretardation of the agent at the place of action. It therefore is one ofthe main ideas of the present invention to transfer the agent, whichoriginally was already present as a solution or in an easily solublesalt-form and which was used this way according to the state of the art,to a poorly soluble salt-form in a dry layer. The availability of theagent is then determined by a dissolution equilibrium between originallyfree agent and the agent present in the form of an insoluble salt. Ifnow in the aqueous medium the agent, which, according to the solubilityproduct of the poorly soluble salt-agent is freely available, diffusesout of the coating, the equilibrium is shifted toward the free agent andthereby a gradual release of the agent out of the poorly soluble saltagent occurs. With other words, a dissolution equilibrium is upstream(advanced) with respect to the diffusion equilibrium and the release ofthe agent out of the poorly soluble salt agent replaces the diffusion asthe rate-determining step of the release of the agent. A prerequisitefor the use of this concept is the ability of the bisphosphonate to formin aqueous medium poorly soluble salts with corresponding anionic orkationic reaction partners of the amphiphilic ionic or water-solubleionic polymeric components, respectively, suggested according to theinvention.

In said salts of amino-bisphosphonates and the amphiphilic ionic, i.e.anionic component, specifically the long-chain alkane-sulfates, or-carboxylates, the according bisphosphonate forms the kationiccomponent, and the amphiphilic ionic or water-soluble ionic polymericcomponent, respectively, specifically the according long-chaincarboxylate or alkane-sulfate, respectively, forms the anioniccomponent. Furthermore, it has been found that by the simultaneous orsubsequent addition of a water-soluble salt, as e.g. a calcium- and/orstrontium salt, the solubility of the respective salt ofamino-bisphosphonates and long-chain carboxylic acid salts or long-chainalkane-sulfates in water can be further decreased. The use of long-chaincarboxylic acids and long-chain alkyl-sulphuric acids instead of theaccording water-soluble salt forms is also within the scope of theinvention.

The invention is further based, as mentioned above, among other things,on the surprising finding that amino-bisphosphonates together withwater-soluble ionic polymers, which are derived from as such knownbiologically compatible (bio-) polymers, form bisphosphonate polymersalts which have a low solubility in water, and which also adhere tonon-metallic or metallic surfaces without further layer-forming means ora support (carrier) being necessary. Said salts of amino-bisphosphonatesand long-chain carboxylic acids or long-chain alkane-sulfates as well assaid bisphosphonate-polymer salts are suited as coatings fornon-metallic or metallic surfaces and release bisphosphonate in aretarded fashion in aqueous medium.

It is e.g. an aspect of the invention that said salts ofamino-bisphosphonates and long-chain carboxylic acids or long-chainalkane-sulfates, as well as said bisphosphonate-polymer salts can beapplied as finely distributed suspensions of water or easily volatile,organic solvents, such as e.g. of chloroform or chloroform-mixtures, bya coating process, therefore for example by dipping, spraying ordripping onto non-metallic or metallic surfaces, whereby they formcoatings with a good adhesion.

Preferably, the coating is a coating which is present without anadditional support or additional carrier, respectively. With otherwords, the coating essentially or even completely comprises only saidcomposite salts. This significantly facilitates the production of suchimplants. Surprisingly, it namely shows that the suggested compositesalts can be applied directly as a coating, as opposed to other agents,and that an additional specific support or carrier is not necessary.

The coating can be applied in a suitable solvent by dipping, spraying,or dripping onto the surface to be coated, and after volatilization orevaporation of the solvent a bisphosphonate-containing coating which hasa low solubility in water is formed by in situ salt formation.

The coating therefore is preferably, among other things, characterizedin that after introduction into the human or animal tissue or into thehuman or animal bone, respectively, it releases the bisphosphonate in adelayed (retarded, sustained release) fashion over a longer time spaninto the immediately surrounding environment of the implant, or showsits efficacy in the immediate surrounding environment of the implant,respectively.

According to a first preferred embodiment, the mixture or the compositesalt, respectively, has a solubility in pure water of less than 1 mg/mlat room temperature, preferably in the range of 0.05-0.9 mg/ml at roomtemperature.

As an implant within the meaning of this invention, each supportstructure shall be understood, which is preferably suitable for use inor embedding in, respectively, and/or on human or animal tissue or bone,respectively. Dental implants are thereby explicitely excluded. Theimplant can have an even (smooth) or roughened surface. It can be porousor non-porous, the latter with open pores which penetrate the entirestructure or with an only superficial porosity. It can be anon-reinforced or reinforced support structure, for example afibre-reinforced support structure. Such implants can for instance beselected from the group of: vessel prosthesis, bone replacementmaterial, bone support material, scaffold, film, pin, thorn, rack, nail,wire, screw, plate, tube, hose, polymeric foam component with open porestructure, fibre, fabric, prostheses, especially joint prostheses, nets,cages, metal foams, porous metallic and ceramic coatings, allogenic andxenogenic implants, cardiovascular implants, artificial ligaments,artificial invertebral disks, introcorneal and intraocular implants,cochlear prostheses, active implants, electrodes and/or combinationsthereof. Furthermore, the implant can even be designed partially orfully bio-degradable.

In principle, support structures are preferred which are supposed to beprovided for the animal or human body middle-term or long-term. However,it is also possible to apply the coating according to the invention tostructures which are provided in the body only temporarily and possiblyonly for a timely delayed release of bisphosphonate. Accordingly, theimplant according to the invention can also be for instance coatedspheres, fibres, fabric, film or similar. Especially in this context, itis also possible to design the actual support structure in abio-degradable fashion, such that is does not have to be removedpost-operatively after the successive release of the agent, but isdissolvable and degradable by the body on its own. Thereby, the coatingsaccording to the invention can be deposited on such bio-degradablematerials, for instance after a general invasion in the area of theoperated bone, where they successively release the agent as long as itis necessary in this zone, and are subsequently degraded by the body.

A further preferred embodiment is characterized in that thebisphosphonate is an amino-bisphosphonate. Such as for examplepamidronic acid, alendronic acid, neridronic acid, risedronic acid,zoledronic acid, olpadronic acid, ibandronic acid, minodronic acid, orcimadronic acid or a mixture and/or alkali- or earth alkali saltsthereof. The already known components pamidronic acid and/or alendronicacid have been shown to be especially effective, possibly in the form ofthe alkali- or earth-alkali salt, such as for examplesodium-alendronate, or sodium-pamidronate, respectively. Generally, itis preferred if the bisphosphonate is present in the free phosphonicacid form, the sodium-, potassium-, ammonium-, calcium-, magnesium-and/or strontium salt form.

According to a further preferred embodiment the amphiphilic component,which is the reason for a reduced solubility of the bisphosphonate inthe composite salt with the bisphosphonate, is at least one componentselected from the group of the linear unsubstituted CI0-C20alkyl-carboxylates or alkyl-sulfates, or their alkali- or earth alkalisalts, respectively, preferably laurate, stearate, palmitate, myristate,oleate, behenate, dodecylsulfate, preferably as alkali- or earth alkalisalts or mixtures thereof.

According to another preferred embodiment the water-soluble ionicpolymeric component, which in the composite salt with the bisphosphonateis the reason for a reduced solubility of the bisphosphonate, is apolymeric component with free anionic groups, preferably a polymericcomponent, which is derived from biologically compatible biopolymers.Thus, the water-soluble ionic polymeric component can preferably becarboxylated, carboxymethylated, sulphated, or phosphorylated derivatesof natural polysaccharides, more preferably of polysaccharides selectedfrom dextran, pullulane, chitosan, starch, or cellulose, or mixturesthereof.

Preferably, the bisphosphonate preferentially selected asamino-bisphosphonate and the amphiphilic component preferentiallyselected as an alkyl-sulfate or alkyl-carboxylate, are present in thecoating in a molar ratio of between 10:1 and 1:5, more preferably in amolar ratio of 2:1 to 1:2. Accordingly, the bisphosphonate selected asamino-bisphosphonate and the water-soluble ionic polymeric component arepresent in the coating preferably in a molar ratio between 10:1 and 1:5,more preferably in a molar ratio of 2:1 to 1:2, each with respect to theamino groups of the amino group-containing bisphosphonate used and theanionic groups present in the polymeric component. Such a coating can beapplied to an even (smooth), porous and/or roughened surface. Thesurface structure can therein be produced by mechanical processes (e.g.sand blasting) and/or by chemical processes (e.g. acid treatment) and/orover chemo-physical processes as e.g. plasma injections.

Basically, this coating is applicable to implants according to the stateof the art, such as for example to an implant on a metallic and/orceramic basis. It thereby shows that the coating is not dependent on aspecific underlying layer or an additional support/carrier in order toimmobilize the bisphosphonate, which significantly facilitates theproduction and makes it more cost-efficient. Accordingly, the coatingcan be applied to such an implant directly and without an intermediatelayer. The implant preferably is for example an implant on the basis ofcalcium-phosphate-ceramics, bioglass, glass-ceramics, calcium-carbonate,calcium-sulfate, organic and preferably absorbable polymers, orcomposites of said materials, or on the basis of pure titanium, titaniumalloys, cobalt-chromium-alloys or stainless steel, or on the basis ofnative elements such as collagen, gelatine, or materials of allogenicorigin.

Preferably, the coating has a thickness in the range of 0.1-10 μm,preferably of 0.5-5 μm.

Furthermore, the present invention concerns a process for the productionof an implant, preferably of the type described above. Therein, asuspension or solution, which contains a bisphosphonate of the generalformula, as indicated above, as well as at least one amphiphiliccomponent, as indicated above, and/or a water-soluble ionic polymericcomponent, as mentioned above, is produced, and the coating is appliedto the surface to be coated of the implant by dipping, spraying, ordripping of this suspension or solution (or the suspension- or solventmixture, respectively) and a coating which has a low solubility in wateris formed after vaporization or evaporation of the suspension means orsolvent (or suspension- or solvent mixture).

The coating can therein either be produced in that in a first coatingstep a solution, e.g. of an amino-bisphosphonate in a suitable solvent,is applied to the surface to be coated by dipping, spraying or dripping,and that after vaporization or evaporation of the solvent in a secondcoating step an amphiphilic and/or polymeric component in a suitablesolvent is applied to the surface to be coated by dipping, spraying ordripping and that after vaporization or evaporation of the secondsolvent a bisphosphonate-containing coating, which has a low solubilityin water, is formed by in situ salt formation.

However, it is also possible to first produce the two components in anaqueous solution, to precipitate them therefrom and subsequently toapply them by said methods together with a suitable solvent orsuspension means. Thereby, for example the bisphosphonate and theamphiphilic component and/or the water-soluble ionic polymeric componentcan be produced, in that bisphosphonate solubilized in water is mixedwith amphiphilic component solubilized in water or water-soluble ionicpolymeric component, respectively, and, that possibly after the additionof additional salts, as for example calcium chloride, the precipitationproduct is isolated as a composite salt, and subsequently this compositesalt is solubilized in a suspension means or solvent (e.g. org. solvent,such as chloroform or also water) or a suspension- or solvent mixture orsuspended therein, respectively. The additional salt, which is used forthe precipitation, can be used therein e.g. at a ratio of bisphosphonate: additional salt of in the range of 1:2 to 2:1.

The drying of the coated implants can be carried out by a known dryingprocess, therefore for example by drying in a gas stream or by the useof vacuum and/or increased temperature. According to the invention, theapplication of both solutions can also be carried out in the oppositeorder. Preferably, it is additionally possible to apply the compositesalt to a pre-warmed implant, e.g. at a temperature of the implant ofmore than 70 degrees Celsius.

According to the invention, non-metallic and metallic and native implantsurfaces can be coated with the described bisphosphonate-containingcompositions. In the first case, materials of aluminium oxide-,zircon-oxide, calcium phosphate ceramics, bioglass or glass ceramics ormixtures of these ceramics and preferably absorbable polymers areespecially preferred. In the second case, they are made of pure metalsor metal alloys normally used in implant medicine, such as for examplepure titanium, titanium alloys, cobalt-chromium-alloys or stainlesssteel. The native materials can for example also be made of collagenscaffolds or allograft implants.

The use of implants with a structured surface is especially preferred.

According to a preferred embodiment of the method according theinvention, the concentrations of the coating solutions containing theamino-bisphosphonate and the amphiphilic and/or the polymeric component,are selected such that in the coating formed by in situ salt formationthe (amino-)bisphosphonate and the amphiphilic component or thepolymeric component, respectively, are present in a molar ratio between10:1 and 1:5, preferably between 2:1 and 1:2.

As a suspension means or solvent, or suspension- or solvent mixture,besides water one or more organic suspension means and/or solvents canbe used, such as e.g. chloroform as a suspension means or a mixture ofchloroform and triethylenglycol in the ratio of 97.5:2.5 as a solvent.

Furthermore, the present invention concerns a bisphosphonate-containingcomposition with a low solubility in aqueous environment, in the form ofa composite salt. This composition contains a bisphosphonate of thegeneral formula (H₂O₃P)—C(X)(Y)—(PO₃H₂), wherein X is selected from H,OH, Cl, F, or a methyl group, Y is selected from H, Cl, F, NH₂, or alinear or a branched C1-C20 alkyl group (preferably C1-C10 or C1-C7),which is unsubstituted or preferably substituted by NH₂, N(CH₃)₂,NH(CH₃), N(CH₃)₃, pyridinyl or imidazolyl, wherein one or more carbonatoms can be replaced by hetero atoms selected from the group NR¹, S orO, wherein R¹ is selected from H or CH₃, with the proviso that no twohetero atoms are interconnected, or pharmaceutically compatible salts oresters of the latter, in addition to at least one amphiphilic componentselected from the group of branched or linear, substituted orunsubstituted, saturated or partially unsaturated C10-C30 alkyl-,alkenyl-, alkylaryl-, aryl-, cycloalkyl-, alkylcycloalkyl-,alkylcykloaryl-carboxylates, -phosphates, or -sulfates or mixturesthereof, and/or a water-soluble ionic polymeric component.

Preferably, Y is a linear C1-C7 alkyl group substituted by NH₂, N(CH₃)₂,NH(CH₃), N(CH₃)₃, pyridinyl or imidazolyl. The amphiphilic componentmore preferably is a linear unsubstituted C10-C20 alkyl-carboxylate oralkyl-sulfate.

The composite salt therein preferably has a solubility in pure water ofless than 1 mg/ml at room temperature, more preferably of in the rangeof less than 0.05-0.9 mg/ml at room temperature. Preferably, thebisphosphonate is an amino-bisphosphonate, preferably pamidronic acid,alendronic acid, neridronic acid, risedronic acid, zoledronic acid,olpadronic acid, ibandronic acid, minodronic acid or cimadronic acid ora mixture and/or alkali- or earth alkali salts thereof, whereinespecially pamidronic acid and/or alendronic acid, possibly in the formof the alkali or earth alkali salt is preferred, and that preferentiallythe bisphosphonate is present in the free phosphonic acid form, thesodium-, potassium-, ammonium-, calcium-, magnesium- and/or strontiumsalt form.

Furthermore, it is preferred that the amphiphilic component is at leastone component selected from the group of the linear unsubstituted C8-C20alkyl-carboxylates or alkyl-sulfates, or their alkali- or earth alkalisalts, respectively, especially preferred laurate, stearate, palmitate,myristate, oleate, behenate, dodecylsulfate, preferably as alkali- orearth alkali salts or mixtures thereof, or the water-soluble ionicpolymeric component is a polymeric component with free anionic groups,respectively, especially preferred a polymeric component, which isderived from biologically compatible biopolymers, wherein thewater-soluble ionic polymeric component preferably is a carboxylated,carboxymethylated, sulphated or phosphorylated derivative of naturalpolysaccharides, more preferably polysaccarides selected from dextran,pullulans, chitosan, starch, or cellulose, or mixtures thereof.

Furthermore, the present invention concerns a use of a composition asdescribed above, for the coating of non-metallic, metallic, polymeric,ceramic, or native implant surfaces, wherein the implant surfaces can beeven (smooth), structured and/or porous.

Further preferred embodiments of the invention are outlined in thedependent claims.

SHORT DESCRIPTION OF THE FIGURE

The invention shall be further illustrated by embodiments in connectionwith the figure. FIG. 1 shows the turning-out torque for implants withvarious different surfaces.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples are for the purpose of further illustrating theinvention without limiting the same. Variations of the introducedembodiments, as they are comprised by the following claims, areavailable to the person skilled in the art within the scope of histechnical professional knowledge, and accordingly the embodimentsdepicted below shall not be used for the limitation of the scope ofprotection provided by the claims, but shall only be interpreted forsupportive purposes.

Production of an Alendronic Acid Stearate Salt 100 mg (0.3076 mmol) ofsodium alendronate are solubilized in 10 ml of water at 80° C. and addedto a solution of 94.3 mg (0.3076 mmol) of sodium stearate in 5 ml ofwater (solubilized at 80° C.). The milky suspension formed thereby isstirred for over 18 hours at 80° C. under inert conditions. Thesuspension is subsequently centrifuged for 10 min at 14000 U/min. Afterremoval of the supernatant the precipitate is washed with distilledwater and is dried in the desiccator under vacuum (10 mbar) at roomtemperature for at least 2 days. The final product was received with ayield of 30%.

Production of a calcium pamidronate stearate

20 mg (0.0717 mmol) of disodium pamidronate are solubilized in 5 ml ofwater and 21.97 mg (0.0717 mmol) of sodium stearate in 5 ml of water at80° C. each. Both clear solutions are mixed and stirred for 30 min at80° C. After the addition of 1M calcium chloride solution (ratiopamidronate:stearate:CaCl₂=1:1:1) a milky white suspension is formed,which is stirred for 18 hours at 80° C. under inert conditions.Subsequently, the precipitate is centrifuged (14000 U/min; 10 min) andthe supernatant is removed.

The remaining precipitate is washed once with distilled water. The finalproduct is dried in the desiccator under vacuum (10 mbar) for at least 2days. The calcium pamidronate stearate is received with a yield of69.3%.

Production of Alendronic Acid Dodecylsulfate

100 mg (0.3076 mmol) of sodium-alendronate are solubilized in 10 ml ofwater at room temperature and added to a solution of 88.7 mg (0.3076mmol) of sodium dodecyl sulphate (SDS) in 5 ml of water (solubilized atRT) and stirred for 30 min at room temperature. After the addition of 1Mcalcium chloride solution at a ratio of alendronate:SDS:CaCl₂=1:1:1, awhite precipitate is released. The suspension is stirred for anadditional 18 hours at room temperature. After centrifugation (14000U/min; 10 min), the clear supernatant is removed and the precipitate iswashed with distilled water. The end product is dried in the desiccatorunder vacuum (10 mbar) at room temperature for at least 2 days. Theachieved yield of alendronic acid dodecylsulfate is 88.4%.

Production of a Calcium Alendronic Acid Carboxymethyldextrane Salt 50 mg(0.15378 mmol) of sodium alendronate (solubilized in 4 ml of water) aremixed with 22.98 mg (0.1038 mmol) of carboxymethyldextrane (CMD) with asubstitution degree of 0.74, solubilized in 1 ml of water, and stirredfor 30 min at room temperature. After the addition of 1M calciumchloride solution at a ratio of alendronate:CMD:CaCl₂=2:1:2, a white,milky precipitate is formed. The suspension was stirred for anadditional 18 hours at room temperature. After centrifugation (14000U/min; 10 min), the clear supernatant is removed and the remainingprecipitate is washed with distilled water. The end product is dried inthe desiccator under vacuum (10 mbar) at room temperature for at least 2days. The ratio of alendronate to CMD was varied from 2:1 to 1:2. Theyields of the respective approaches were 54.2% for 2:1, 44.8% for 1:1,and 12.2% for 1:2.

Coating of Implants

An implant (hip joint implant) on the basis of titanium was firstroughened in the area exposed to the bone by a sand blasting process.Subsequently, a suspension of the above produced alendronic acidstearate salt in chloroform by addition of 0.025 g of the alendronicacid stearate salt to 4.975 g of chloroform (3.3 ml) was produced within10 min under stirring. By treatment with an ultrasound-homogenizer (20Watt total capacity) a homogenous suspension was gained.

The implants were warmed to 80° C. and sprayed with the describedsuspension several times with a conventional spraying pistol (3×).During the spraying process, the implants clamped in a suitable devicerotated evenly around their longitudinal axis. Between the sprayingcycles the implants were dried at 80° C. until the solvent wascompletely evaporated.

Experiments with Animals

The implants thus produced showed an ingrowth behaviour free ofcomplications and an improved osteointegration compared to the implantsaccording to the state of the art. Furthermore, a good integration atthe soft tissue is shown.

FIG. 1 shows corresponding results of experiments conducted with threedifferent surface implant types. Therein, a titanium implant in the formof a pin with a diameter of 4.2 mm and a length of 8 mm was used. Thesurfaces of implant (1) were sand blasted and acid etched without anyfurther coating, while the surfaces of implant (2) were oxidizedplasmachemically anodically without any further coating and the surfacesof implant (3) were sand blasted and acid etched and coated with acoating essentially according to the above described example concerningthe coating of implants (see above: chapter coating of implants) andthen the implants (1), (2), and (3) were compared in an animalexperiment.

The sand blasted, acid etched surface and the plasmachemicallyanodically oxidized surface relate to the surfaces of commerciallyspread and often used implants.

The implants were implanted into the pelvis of sheep. After a recoveryperiod of 2 weeks, the turning-out torque necessary in order to releasethe ingrown implants from the bone was determined in Nmm. As FIG. 1shows, a significantly improved ingrowth of the implant (3) coatedaccording to the invention is achieved.

1. Implant, excluding a dental implant, which comprises a coating at least in surface areas which are at least in indirect contact with hard and/or soft tissue when implanted, which coating comprises a bisphosphonate of the general formula (H₂O₃P)—C(X)(Y)—(PO₃H₂)  (1) wherein X is selected from H, OH, Cl, F, or a methyl group Y is selected from H, Cl, F, NH₂ or a linear or branched C1-C20 alkyl group, which is unsubstituted or substituted by a group selected from NH₂, N(CH₃)₂, NH(CH₃), N(CH₃)₃, pyridinyl or imidazolyl, wherein one or more carbon atoms can be replaced by hetero atoms selected from the group NR¹, S or O, wherein R¹ is selected from H or CH₃, with the proviso that no two hetero atoms are interconnected, or pharmaceutically compatible salts or esters thereof, in addition to at least one amphiphilic component selected from the group of the branched or linear, substituted or unsubstituted, saturated or partially unsaturated C10-C30 alkyl-, alkenyl-, alkylaryl-, aryl-, cycloalkyl-, alkylcycloalkyl-, alkylcykloaryl - carboxylates, -phosphates, or -sulfates or mixtures thereof, and/or a water-soluble ionic polymeric component.
 2. Implant according to claim 1, wherein Y is a linear C1-C7 alkyl group substituted by a group selected from NH₂, N(CH₃)₂, NH(CH₃), N(CH₃)₃, pyridinyl or imidazolyl, and wherein preferably the amphiphilic component is a linear unsubstituted C10-C20 alkyl-carboxylate or alkyl-sulfate.
 3. Implant according to claim 1, wherein in the coating the bisphsphonate and the amphiphilic component or the bisphosphonate and the water-soluble ionic polymeric component, respectively, is present as a mixture, preferably as a composite salt of low solubility in water.
 4. Implant according to claim 3, wherein—the mixture or the composite salt, respectively, has a solubility in pure water of less than 1 mg/ml at room temperature, preferably of in the range of from less than 0.05-0.9 mg/ml at room temperature.
 5. Implant according to claim 1, wherein the implant is a smooth or roughened, porous or non-porous, reinforced or non-reinforced support structure, preferably selected from the group: vessel prosthesis, bone replacement material, bone support material, scaffold, film, pin, thorn, rack, nail, wire, screw, plate, tube, hose, polymeric foam component with open pore structure, fibre, fabric, prostheses, especially joint prostheses, nets, cages, metal foams, porous metallic and ceramic coatings, allogenic and xenogenic implants, cardiovascular implants, artificial ligaments, artificial invertebral discs, introcorneal and intraocular implants, cochlear prostheses, active implants, electrodes and/or combinations thereof.
 6. Implant according to claim 1, wherein the bisphosphonate is an amino-bisphosphonate, preferably pamidronic acid, alendronic acid, neridronic acid, risedronic acid, zoledronic acid, olpadronic acid, ibandronic acid, minodronic acid, or cimadronic acid, or a mixture and/or alkali- or earth alkali-salts thereof, and wherein especially pamidronic acid and/or alendronic acid, possibly in the form of the alkali- or earth alkali-salt is preferred.
 7. Implant according to claim 1, wherein the bisphosphonate is present in the free phosphonic acid form, the sodium-, potassium-, ammonium-, calcium-, magnesium- and/or strontium-salt form.
 8. Implant according to claim 1, wherein the amphiphilic component is at least one component selected from the group of the linear unsubstituted C10-C20 alkyl-carboxylates or alkyl-sulfates, or their alkali- or earth alkali-salts, respectively, preferably laurate, stearate, palmitate, myristate, oleate, behenate, dodecylsulfate, preferably as alkali- or earth alkali-salts or mixtures thereof.
 9. Implant according to claim 1, wherein the water-soluble ionic polymeric component is a polymeric component with free anionic groups, preferably a polymeric component, which is derived from biologically compatible biopolymers.
 10. Implant according to claim 9, wherein the water-soluble ionic polymeric component is a carboxylated, carboxymethylated, sulphated or phosphorylated derivative of natural polysaccharides, preferably of polysaccharides selected from dextran, pullulans, chitosan, starch or cellulose, or mixtures thereof.
 11. Implant according to claim 1, wherein the bisphosphonate, selected preferably as amino-bisphosphonate, and the amphiphilic component, selected preferably as alkyl-sulfate or alkyl-carboxylate, are present in the coating in a molar ratio between 10:1 and 1:5, preferably in a molar ratio from 2:1 to 1:2.
 12. Implant according to claim 1, wherein the bisphosphonate selected as amino-bisphosphonate and the water-soluble ionic polymeric component are present in the coating in a molar ratio between 10:1 and 1:5, preferably in a molar ratio from 2:1 to 1:2, each with respect to the amino groups of the amino group-containing bisphosphonate used and the anionic groups of the polymeric component which are present.
 13. Implant according to claim 1, wherein the coating is applied to an even, porous and/or roughened surface without a support or carrier.
 14. Implant according to claim 1, wherein the implant concerns an implant of a metallic and/or ceramic and/or polymeric and/or native basis, wherein preferably the coating is applied to such an implant directly and without an intermediate layer, and wherein the implant preferably is selected from the sroup of calcium phosphate ceramics, bioglass, glass ceramics, calcium carbonate, calcium sulphate, organic polymers, or composites of said materials, or implant surfaces of pure titanium, titanium alloys, cobalt-chromium alloys or stainless steel, or native implant surfaces, which are composed of collagen, gelatine or materials of allogenic origin.
 15. Implant according to claim 1, wherein after introduction into the human or animal tissue, or the human or animal bone, respectively, the coating releases the bisphosphonate in a delayed manner into the environment.
 16. Implant according to claim 1, wherein the coating has a thickness in the range of 0.1-10, preferably of 0.5-5 μm.
 17. Implant according to claim 1, wherein the implant concerns a dry, essentially solvent-free and essentially water-free coating.
 18. Implant according to claim 1, wherein the amphiphilic component has anionic character, wherein it preferably has a monovalent or bivalent negative charge.
 19. Implant according to claim 1, wherein the coating is applied as a slurry or suspension in an organic solvent, preferably in a spraying- or dipping process and subsequently completely dried.
 20. Method for producing an implant according to claim 1, wherein a suspension or solution or a suspension- or solvent-mixture is produced, which contains a bisphosphonate of the general formula (H₂O₃P)—C(X)(Y)—(PO₃H₂)  (I) wherein X is selected from H, OH, Cl, F, or a methyl group Y is selected from H, Cl, F, NH₂ or a linear or branched C1-C20 alkyl group, which is unsubstituted or substituted by a group selected from NH₂, N(CH₃)₂, NH(CH₃), N(CH₃)₃, pyridinyl or imidazolyl, wherein one or more carbon atoms can be replaced by hetero atoms selected from the group NR¹, S or O, wherein R¹ is selected from H or CH₃, with the proviso that no two hetero atoms are interconnected, or pharmaceutically compatible salts or esters thereof, in addition to at least one amphiphilic component selected from the group of the branched or linear, substituted or unsubstituted, saturated or partially unsaturated C10-C30 alkyl-, alkenyl-, alkylaryl-, aryl-, cycloalkyl-, alkylcycloalkyl-, alkylcykloaryl -carboxylates, -phosphates, or -sulfates or mixtures thereof, and/or a water-soluble ionic polymeric component, and wherein the coating is applied to the implant surface to be coated by dipping, spraying, or dripping of this suspension or solution or the suspension- or solvent-mixture and wherein after volatilization or evaporation of the suspension or solution or the suspension- or solvent-mixture, respectively, a bisphosphonate-containing coating is formed which has a low solubility in water.
 21. Method according to claim 20, wherein in a first coating step a solution of an amino-bisphosphonate in a suitable solvent is applied to the surface to be coated by dipping, spraying, or dripping, and wherein after volatilization or evaporation of the solvent in a second coating step an amphiphilic and/or polymeric component in a suitable solvent is applied to the previously coated surface by dipping, spraying, or dripping, and wherein after volatilization or evaporation of the second solvent a bisphosphonate-containing coating, which has a low solubility in water, is formed by in situ salt formation.
 22. Method according to claim 20, wherein the concentrations of the coating solutions containing the amino-bisphosphonate and the amphiphilic and/or the polymeric component are chosen such that in the coating formed by in situ-salt formation the amino-bisphosphonate and the amphiphilic component are present in a molar ratio between 10:1 and 1:5, preferably between 2:1 and 1:2.
 23. Method according to claim 20, wherein the bisphosphonate and the amphiphilic component and/or the water-soluble ionic polymeric component are produced by mixing bisphosphonate solubilized in water with amphiphilic component solubilized in water or water-soluble ionic polymeric component, respectively, and, possibly after the addition of additional salts, as for example calcium chloride, the precipitation product is isolated as a composite salt, and subsequently this composite salt is solubilized in a suspension means or solvent or a suspension- or solvent mixture or suspended therein, respectively.
 24. Method according to claim 20, wherein water or one or more organic suspension means and/or solvents are used as suspension means or solvents or suspension- or solvent mixtures, such as e.g. chloroform as a suspension means or a mixture of chloroform and triethyleneglycol preferably in the ratio of 97.5:2.5 as a solvent.
 25. Method according to claim 20, wherein the coating is applied as a slurry or suspension in an organic solvent, preferably in a spraying- or dipping process and subsequently completely dried.
 26. Bisphosphonate-containing composition of a low solubility in an aqueous environment, in the form of a composite salt, which contains a bisphosphonate of the general formula (H₂O₃P)—C(X)(Y)—(PO₃H₂)  (I) wherein X is selected from H, OH, Cl, F, or a methyl group Y is selected from H, Cl, F, NH₂ or a linear or branched C1-C20 alkyl group, which is unsubstituted or substituted by a group selected from Cl, F, NH₂, N(CH₃)₂, NH(CH₃), N(CH₃)₃, pyridinyl or imidazolyl, wherein one or more carbon atoms can be replaced by hetero atoms selected from the group NR¹, S or O, wherein R¹ is selected from H or CH₃, with the proviso that no two hetero atoms are interconnected, or pharmaceutically compatible salts or esters thereof, in addition to at least one amnphiphilic component selected from the group of branched or linear, substituted or unsubstituted, saturated or partially unsaturated C10-C30 alkyl-, alkenyl-, alkylaryl-, aryl-, cycloalkyl-, alkylcycloalkyl-, alkylcykloaryl-carboxylates, -phosphates, or -sulfates or mixtures thereof, and/or a water-soluble ionic polymeric component.
 27. Composition according to claim 26, wherein the composite salt has a solubility in pure water of less than 1 mg/ml at room temperature, preferably of in the range of less than 0.05-0.9 mg/ml at room temperature.
 28. Composition according to claim 26, wherein the bisphosphonate is an amino-bisphosphonate, preferably selected from the group of pamidronic acid, alendronic acid, neridronic acid, risedronic acid, zoledronic acid, olpadronic acid, ibandronic acid, minodronic acid or cimadronic acid, or a mixture and/or alkali- or earth alkali salts thereof, wherein pamidronic acid and/or alendronic acid, possibly in the form of the alkali- or earth alkali salt, is preferred, and wherein preferably the bisphosphonate is present in a form selected from the free phosphonic acid form, the sodium-, potassium-, ammonium-, calcium-, magnesium- and/or strontium salt form.
 29. Composition according to claim 26, wherein the amphiphilic component is at least one component selected from the group of the linear unsubstituted C10-C20 alkyl-carboxylates or alkyl-sulfates, or their alkali- or earth alkali-salts, respectively, preferably laurate, stearate, palmitate, myristate, oleate, behenate, dodecylsulfate, preferably as alkali- or earth alkali salts or mixtures thereof, or wherein the water-soluble ionic polymeric component is a polymeric component derived from biologically compatible biopolymers, respectively, and wherein the water-soluble ionic polymeric component preferably is a carboxylated, carboxymethylated, sulphated or phosphorylated derivate of natural polysaccarides, preferably of polysaccharides selected from dextran, pullulans, chitosan, starch or cellulose, or mixtures thereof.
 30. Method for using a composition according to claim 26 for the coating of non-metallic, metallic or native, preferably smooth, structured and/or porous implant surfaces. 